Tolterodine, the generic name of the compound (R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenylpropylamine, occasionally identified as (R)-tolterodine, is a muscarinic receptor antagonist useful in the treatment of urinary incontinence and other symptoms of urinary bladder hyperactivity. The (S) enantiomer, also known as (S)-tolterodine, and its use in treating urinary and gastrointestinal disorders, has been disclosed in patent document WO 98/03067. U.S. Pat. No. 6,538,035 discloses the use of tolterodine and some of its derivatives in treating asthma in mammals.
Tolterodine was first disclosed in U.S. Pat. No. 5,382,600. Said patent discloses several methods for preparing tolterodine and analogues, generally based on displacing a tosylate with diisopropylamine. Said process has several drawbacks. The displacement reaction occurs very slowly, so several days are required to carry out said reaction, and the total yields are low. Some of the reagents used, such as methyl iodide and lithium and aluminum hydride, are expensive and their use implies a hazard. This makes the overall process more expensive and rather unproductive.
An alternative process for obtaining tolterodine is disclosed in U.S. Pat. No. 5,922,914. Said process comprises reducing 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one with DIBAL (diisobutylaluminum hydride) in toluene to give the corresponding hemiketal 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-ol which is then subjected to reductive amination to give racemic tolterodine. This process also has some disadvantages since it uses the reagent DIBAL, which is expensive and hazardous, so carrying out the invention to practice is not suitable at the industrial level.
Patent application WO 03/014060 discloses a process for obtaining tolterodine which, though it partially overcomes some drawbacks of the previous processes, it still includes problematic steps, particularly obtaining the intermediate 3-(2-methoxy-5-methylphenyl)-3-phenylpropanol, its conversion into the tosylate derivative and the subsequent displacement of tosylate with diisopropylamine. These steps still have serious problems, such as the steric hindrance of diisopropylamine in the tosylate displacement reaction, which makes the nucleophilic substitution reaction more difficult, the high temperatures needed for the same, as well as the long reaction times they comprise, even days.
A different approach for preparing the (R)-tolterodine enantiomer consists of several enantioselective syntheses such as those disclosed in U.S. Pat. No. 6,310,248, or by Andersson et al. in J. Org. Chem. 1998, 63, 8067-8070, which disclose processes requiring the participation of asymmetry inducers or chiral auxiliaries, respectively, which are generally very expensive reagents.
It is therefore necessary to solve the problems associated with processes belonging to the state of the art and to provide an alternative process for obtaining tolterodine which improves the cost of the process using more cost-effective and less hazardous reagents and starting materials and which is therefore more productive. Said process must advantageously be susceptible to applying on an industrial scale and must provide the desired product with a good yield and quality.